In Vitro and Computational Studies of Perezone and Perezone Angelate as Potential Anti-Glioblastoma Multiforme Agents.

Maricarmen Hernández-Rodríguez,Pablo I Mendoza Sánchez,René Miranda Ruvalcaba,Joel Martínez,Dorota Maciejewska,Elvia Mera Jiménez,María I Nicolás-Vázquez,Teresa Żołek,Erika Rosales Cruz,Martha E Macías Pérez

doi:10.3390/molecules27051565

Abstract

Glioblastoma multiforme (GBM) represents the most malignant type of astrocytoma, with a life expectancy of two years. It has been shown that Poly (ADP-ribose) polymerase 1 (PARP-1) protein is over-expressed in GBM cells, while its expression in healthy tissue is low. In addition, perezone, a phyto-compound, is a PARP-1 inhibitor with anti-neoplastic activity. As a consequence, in the present study, both in vitro and computational evaluations of perezone and its chemically related compound, perezone angelate, as anti-GBM agents were performed. Hence, the anti-proliferative assay showed that perezone angelate induces higher cytotoxicity in the GBM cell line (U373 IC50 = 6.44 μM) than perezone (U373 IC50 = 51.20 μM) by induction of apoptosis. In addition, perezone angelate showed low cytotoxic activity in rat glial cells (IC50 = 173.66 μM). PARP-1 inhibitory activity (IC50 = 5.25 μM) and oxidative stress induction by perezone angelate were corroborated employing in vitro studies. In the other hand, the performed docking studies allowed explaining the PARP-1 inhibitory activity of perezone angelate, and ADMET studies showed its probability to permeate cell membranes and the blood–brain barrier, which is an essential characteristic of drugs to treat neurological diseases. Finally, it is essential to highlight that the results confirm perezone angelate as a potential anti-GBM agent.

Highlights

Glioblastoma multiforme (GBM) represents the most malignant type of astrocytoma, which is distinguished by its high ability to produce metastasis
Compared with the recommended values of the unbound drug to proteins within blood plasma (%Unbnd) > 10%, the results showed a higher percentage of non-bound parts for perezone angelate than for perezone itself, indicating that they can circulate more freely within the bloodstream and can have access to the target site
Cell proliferation demonstrated that treatment with perezone angelate significantly induces apoptosis in U373 cells, with low cytotoxicity in rat glial cells, being apoptosis the type of cell death

Summary

Introduction

Glioblastoma multiforme (GBM) represents the most malignant type of astrocytoma, which is distinguished by its high ability to produce metastasis. Patients with GBM have the worst prognosis [1–4]. GBM treatment includes surgery, radiotherapy, and chemotherapy, which have shown minimal improvements [5]. Local GBM infiltration into normal tissue results in tumor recurrence, culminating with the patient’s death [6]. Chemotherapy represents a valuable tool to treat GBM.

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Discussion

Conclusion